Morbidity and mortality secondary to cardiovascular disease is the major health problem in obese patients. Obese patients are burdened with an array of metabolic dysfunctions associated with excess weight. Most notable of these is insulin resistance which causes deleterious changes in plasma chemistry, compensatory over-production of insulin and eventual failure of the pancreatic 2-cell and Type 2 diabetes. Because obese patients present with both metabolic and cardiovascular dysfunction, it is widely suspected that the two are dependent variables. The extent to which this is true and the mechanisms linking metabolic and cardiovascular disease are unknown. In preliminary data for this application, we have generated a novel mouse model in which an insulin receptor desensitizing gene, protein tyrosine phosphatase 1B (PTP1B) is deleted from obese mice. The result is a mouse with persistent obesity and correction of peripheral insulin resistance. Obese mice show impairment of microvascular endothelial NO-mediated vasodilation in vitro, a defect corrected by PTP1B deletion. This suggests that insulin resistance is the causal aspect of obesity-induced metabolic dysfunction. The molecular mechanisms underlying these microvascular defects will be determined in Aim 1. The cardiovascular impact of correcting insulin resistance in obese mice will be determined in Aim 2, using blood flow, blood pressure and vascular remodeling as endpoints. While preliminary data provides novel evidence that insulin resistance and cardiovascular dysfunction are linked, the nature of this relationship is unclear. High levels of HbA1c in obese mice suggest an environment favorable to non-enzymatic glycation and this association is strengthened by the increased expression of the Receptor for Advanced Glycation End-products (RAGE). Both deficits are corrected in obese PTP1B null mice with improved insulin resistance. This leads us to the hypothesis that RAGE is the mechanistic link between insulin resistance and cardiovascular dysfunction and this hypothesis will be tested in Aim 3 by the generation of novel dual KO mice, obese mice lacking RAGE. Taken together, these studies will generate new information about the mechanisms, mediators and physiologic impact of obesity-induced metabolic dysfunction. Successful completion of these aims may identify new targets to aid in the treatment of the most common clinical outcomes of obesity. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the greatest health threat in the obese population, in part due to the metabolic dysfunction that accompanies obesity. Studies proposed in the application identify two new therapeutic targets, PTP1B and RAGE, that may uncouple the deleterious relationship between obesity and cardiovascular disease by breaking the "metabolic connection". Completion of these experiments will not only potentially validate these new targets but also better clarify why obesity causes cardiovascular disease.